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Journal of Biochemistry Advance Access originally published online on March 9, 2009
Journal of Biochemistry 2009 146(1):51-60; doi:10.1093/jb/mvp042
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© The Authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

Expression Analysis of the Aldo-Keto Reductases Involved in the Novel Biosynthetic Pathway of Tetrahydrobiopterin in Human and Mouse Tissues

Haruka Hirakawa1, Hiroshi Sawada1, Yumi Yamahama2, Shin-Ichiro Takikawa3, Haruo Shintaku4, Akira Hara5, Keisuke Mase6, Tomoyoshi Kondo7 and Teruhiko Iino1,*

1Department of General Studies, Nihon University, Setagaya-ku, Tokyo 156-8550; 2Department of Biology, Hamamatsu University School of Medicine, Hamamatsu 431-3192; 3Biological Laboratory, Kitasato University, Sagamihara City, Kanagawa 228-8555; 4Department of Pediatrics, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585; 5Laboratory of Biochemistry, Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-8585; 6Research Team of Sericultural Science, National Institute of Agrobiological Science, Matsumoto, Nagano 390-0812; and 7Department of Neurology, Wakayama Medical University, Kimiidera, Wakayama 641-8510, Japan

*To whom correspondence should be addressed. Tel: +81-3-5317-9716; Fax: +81-3-5317-9716; E-mail: iino{at}chs.nihon-u.ac.jp

Received February 3, 2009; Accepted February 27, 2009


  Abstract

Tetrahydrobiopterin (BH4) acts as a cofactor of the aromatic amino-acid hydroxylases, and its deficiency may result in hyperphenylalaninemia (HPA) and decreased production of the neurotransmitters. BH4 is synthesized by sepiapterin reductase (SPR) from 6-pyruvoyl-tetrahydropterin (PPH4). A patient with SPR deficiency shows no HPA; however, an SPR knockout mouse exhibits HPA. We have reported on the SPR-unrelated novel biosynthetic pathway from PPH4 to BH4 (salvage pathway II) in which 3{alpha}-hydroxysteroid dehydrogenase type 2 and aldose reductase work in concert. In this study, we performed the expression analysis of both proteins in humans and wild-type mice. The results of expression analysis indicated that salvage pathway II worked in human liver; however, it did not act in human brain or in mouse liver and brain. For this reason, a patient with SPR deficiency may show progressive neurological deterioration without HPA, and SPR knockout mice may exhibit HPA and abnormal locomotion activity.

Key Words: AKR1B1, AKR1C3, Aldo-keto reductase, BH4 deficiency, SPR deficiency


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